Activity Of Inspiratory Neurons Research Articles

Respiration and Cough in Pompe Disease: Results from a neuromechanical computational model of the respiratory control system

Late Onset Pompe Disease (LOPD) is an incurable, rare progressive genetic disease. It is characterized by glycogen build-up, due to mutations in the gene encoding the lysosomal enzyme acid alpha glucosidase, throughout muscle and neural regions. This accumulation is associated with cell death and muscle fiber swelling, eventually leading to respiratory insuffciency and airway clearance (i.e. cough) deficiency. Impairments in effective airway clearance result from the inability to clear normal pulmonary volume. Emerging evidence indicates significant respiratory neuron dysfunction, altering pulmonary function in humans and animal models. It has been suggested that respiratory and airway clearance insuffciency observed in LOPD may be attributed to medullary motoneurons potentially associated with the respiratory and cough pattern generators (Fuller et al., 2013; DeRuisseau et al., 2009). However, the precise neural mechanisms that suppress breathing and cough are not fully understood. One possible target for LOPD respiratory insuffciencies may be reduced medullary inspiratory neuron activity within this network, which could result in decreased phrenic motoneuron output. Using a stochastic neural network simulator that consisted of discrete “integrate and fire” populations, we simulated a systematic decrease in three medullary inspiratory neuron populations: inspiratory driver (I-Driver), inspiratory decrementing (I-Dec), or inspiratory augmenting (I-Aug) neurons. We simulated breathing and three cough trials. By targeting these populations, we expected global decreased neural bursts, suppressed inspiratory motor drive, and/or suppressed expiratory motoneuron output. Simulations indicated that when the I-Dec motoneuron population decreased by 25%, it resulted in apnea and abolished cough. Reducing the I-Aug motoneuron population by 20% resulted in longer inspiratory phase durations (TI) and a decreased respiratory rate. During cough, there was a decrease in the duration and amplitudes of the expiratory motoneuronal activity associated with decreased cough receptor and pulmonary stretch receptor afferent feedback. When the I-Driver motoneuron population was reduced by 25%, TI decreased and I amplitude increased during respiration. During cough, lumbar and phrenic motoneuron discharge duration and amplitude decreased. These results are consistent with previously reported in vivo data. Overall, our simulation data support the plausibility of glycogen storage dysfunction impairing medullary neuronal and premotoneuronal excitability within the inspiratory network. Our results also suggest that some neurons may be more sensitive to glycogen storage than others within the brainstem inspiratory network. Supported by NHLBI L30HL165496, NIH T32 HL 134621 and 3OT2OD023854. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in pontine and preBötzinger/Bötzinger complex neuronal activity during remifentanil-induced respiratory depression in decerebrate dogs.

Introduction: In vivo studies using selective, localized opioid antagonist injections or localized opioid receptor deletion have identified that systemic opioids dose-dependently depress respiratory output through effects in multiple respiratory-related brainstem areas. Methods: With approval of the subcommittee on animal studies of the Zablocki VA Medical Center, experiments were performed in 53 decerebrate, vagotomized, mechanically ventilated dogs of either sex during isocapnic hyperoxia. We performed single neuron recordings in the Pontine Respiratory Group (PRG, n = 432) and preBötzinger/Bötzinger complex region (preBötC/BötC, n = 213) before and during intravenous remifentanil infusion (0.1-1mcg/kg/min) and then until complete recovery of phrenic nerve activity. A generalized linear mixed model was used to determine changes in Fn with remifentanil and the statistical association between remifentanil-induced changes in Fn and changes in inspiratory and expiratory duration and peak phrenic activity. Analysis was controlled via random effects for animal, run, and neuron type. Results: Remifentanil decreased Fn in most neuron subtypes in the preBötC/BötC as well as in inspiratory (I), inspiratory-expiratory, expiratory (E) decrementing and non-respiratory modulated neurons in the PRG. The decrease in PRG inspiratory and non-respiratory modulated neuronal activity was associated with an increase in inspiratory duration. In the preBötC, the decrease in I-decrementing neuron activity was associated with an increase in expiratory and of E-decrementing activity with an increase in inspiratory duration. In contrast, decreased activity of I-augmenting neurons was associated with a decrease in inspiratory duration. Discussion: While statistical associations do not necessarily imply a causal relationship, our data suggest mechanisms for the opioid-induced increase in expiratory duration in the PRG and preBötC/BötC and how inspiratory failure at high opioid doses may result from a decrease in activity and decrease in slope of the pre-inspiratory ramp-like activity in preBötC/BötC pre-inspiratory neurons combined with a depression of preBötC/BötC I-augmenting neurons. Additional studies must clarify whether the observed changes in neuronal activity are due to direct neuronal inhibition or decreased excitatory inputs.

Fentanyl effects on respiratory neuron activity in the dorsolateral pons.

Opioids suppress breathing through actions in the brainstem, including respiratory-related areas of the dorsolateral pons, which contain multiple phenotypes of respiratory patterned neurons. The discharge identity of dorsolateral pontine neurons that are impacted by opioids is unknown. To address this, single neuronal units were recorded in the dorsolateral pons of arterially perfused in situ rat preparations that were perfused with an apneic concentration of the opioid agonist fentanyl, followed by the opioid antagonist naloxone (NLX). Dorsolateral pontine neurons were categorized based on respiratory-associated discharge patterns, which were differentially affected by fentanyl. Inspiratory neurons and a subset of inspiratory/expiratory phase-spanning neurons were either silenced or had reduced firing frequency during fentanyl-induced apnea, which was reversed upon administration of naloxone. In contrast, the majority of expiratory neurons continued to fire tonically during fentanyl-induced apnea, albeit with reduced firing frequency. In addition, pontine late-inspiratory and postinspiratory neuronal activity were absent from apneustic-like breaths during the transition to fentanyl-induced apnea and the naloxone-mediated transition to recovery. Thus, opioid-induced deficits in respiratory patterning may occur due to reduced activity of pontine inspiratory neurons, whereas apnea occurs with loss of all phasic pontine activity and sustained tonic expiratory neuron activity.NEW & NOTEWORTHY Opioids can suppress breathing via actions throughout the brainstem, including the dorsolateral pons. The respiratory phenotype of dorsolateral pontine neurons inhibited by opioids is unknown. Here, we describe the effect of the highly potent opioid fentanyl on the firing activity of these dorsolateral pontine neurons. Inspiratory neurons were largely silenced by fentanyl, whereas expiratory neurons were not. We provide a framework whereby this differential sensitivity to fentanyl can contribute to respiratory pattern deficits and apnea.

Potential presynaptic effects of opioids on medullary inspiratory circuits: New insights from a joint neural biomechanical model

Administration of opioids can lead to respiratory depression and eventually death. Opioids can alter the frequency and magnitude of inspiratory motor drive by binding to mu‐opioid receptors on inspiratory neurons located in several areas of the brainstem. Lalley (Am J Physiol: Regul. 285:R1287‐1304, 2003) suggested that some of the effects of fentanyl on bulbospinal inspiratory neuron activity were presynaptic. We tested the feasibility of pre‐ vs post‐synaptic effects of opioids with an integrate‐and‐fire computational neural biomechanical model of the brainstem respiratory network. Our previous simulations utilizing this model involved separately reducing conductance at groups of synapses that excited inspiratory‐augmenting (I‐Aug) or inspiratory‐decrementing (I‐Dec) neuron populations to simulate opioid‐mediated decreases in the presynaptic excitability of excitatory axons to these neurons from inspiratory driver neurons (I‐driver). We found that the presynaptic hypothesis was best supported by a mechanism involving depression of the excitatory synapse between I‐driver and I‐decrementing neurons. The current modeling investigation extends that work by focusing on three inspiratory neuron populations: I‐Aug, I‐Dec, and late inspiratory (late‐I). We separately decreased the conductance of each excitatory synapse to examine how these changes would affect the respiratory pattern. Simulations revealed that systematically decreasing the conductance of synapses from the I‐Aug neuron population to late‐I and I‐ Aug bulbospinal populations by 50% resulted in a decrease in frequency, duration, and amplitude of inspiratory drive. Decreasing the conductance of excitatory synapses from I‐Dec neurons to I‐Aug, and late‐I populations had a limited effect on inspiratory activity. Similar results were observed when the conductance of excitatory synapses was reduced from the late‐I population to its I‐Dec and I‐Aug targets. Overall, these results indicate that a plausible mechanism for respiratory suppression by opioids could include depression of excitatory synaptic actions between selected medullary inspiratory neuron populations.

Complex bursting dynamics in an embryonic respiratory neuron model.

Pre-Bötzinger complex (pre-BötC) network activity within the mammalian brainstem controls the inspiratory phase of the respiratory rhythm. While bursting in pre-BötC neurons during the postnatal period has been extensively studied, less is known regarding inspiratory pacemaker neuron behavior at embryonic stages. Recent data in mouse embryo brainstem slices have revealed the existence of a variety of bursting activity patterns depending on distinct combinations of burst-generating INaP and ICAN conductances. In this work, we consider a model of an isolated embryonic pre-BötC neuron featuring two distinct bursting mechanisms. We use methods of dynamical systems theory, such as phase plane analysis, fast-slow decomposition, and bifurcation analysis, to uncover mechanisms underlying several different types of intrinsic bursting dynamics observed experimentally including several forms of plateau bursts, bursts involving depolarization block, and various combinations of these patterns. Our analysis also yields predictions about how changes in the balance of the two bursting mechanisms contribute to alterations in an inspiratory pacemaker neuron activity during prenatal development.

Mecp2 Disruption in Rats Causes Reshaping in Firing Activity and Patterns of Brainstem Respiratory Neurons

People with Rett Syndrome (RTT), a neurodevelopmental disorder caused by mutations in the MECP2 gene, have breathing abnormalities manifested as periodical hypoventilation with compensatory hyperventilation, which are attributable to a high incidence of sudden death. Similar breathing abnormalities have been found in animal models with Mecp2 disruptions. Although RTT-type hypoventilation is believed to be due to depressed central inspiratory activity, whether this is true remains unknown. Here we show evidence for reshaping in firing activity and patterns of medullary respiratory neurons in RTT-type hypoventilation without evident depression in inspiratory neuronal activity. Experiments were performed in decerebrate rats in vivo. In Mecp2-null rats, abnormalities in breathing patterns were apparent in both decerebrate rats and awake animals, suggesting that RTT-type breathing abnormalities take place in the brainstem without forebrain input. In comparison to their wild-type counterparts, both inspiratory and expiratory neurons in Mecp2-null rats extended their firing duration, and fired more action potentials during each burst. No changes in inspiratory or expiratory neuronal distributions were found. Most inspiratory neurons started firing in the middle of expiration and changed their firing pattern to a phase-spanning type. The proportion of post-inspiratory neurons was reduced in the Mecp2-null rats. With the increased firing activity of both inspiratory and expiratory neurons in null rats, phrenic discharges shifted to a slow and deep breathing pattern. Thus, the RTT-type hypoventilation appears to result from reshaping of firing activity of both inspiratory and expiratory neurons without evident depression in central inspiratory activity.

Organotypic slice cultures containing the preBötzinger complex generate respiratory-like rhythms.

Study of acute brain stem slice preparations in vitro has advanced our understanding of the cellular and synaptic mechanisms of respiratory rhythm generation, but their inherent limitations preclude long-term manipulation and recording experiments. In the current study, we have developed an organotypic slice culture preparation containing the preBötzinger complex (preBötC), the core inspiratory rhythm generator of the ventrolateral brain stem. We measured bilateral synchronous network oscillations, using calcium-sensitive fluorescent dyes, in both ventrolateral (presumably the preBötC) and dorsomedial regions of slice cultures at 7-43 days in vitro. These calcium oscillations appear to be driven by periodic bursts of inspiratory neuronal activity, because whole cell recordings from ventrolateral neurons in culture revealed inspiratory-like drive potentials, and no oscillatory activity was detected from glial fibrillary associated protein-expressing astrocytes in cultures. Acute slices showed a burst frequency of 10.9 ± 4.2 bursts/min, which was not different from that of brain stem slice cultures (13.7 ± 10.6 bursts/min). However, slice cocultures that include two cerebellar explants placed along the dorsolateral border of the brainstem displayed up to 193% faster burst frequency (22.4 ± 8.3 bursts/min) and higher signal amplitude (340%) compared with acute slices. We conclude that preBötC-containing slice cultures retain inspiratory-like rhythmic function and therefore may facilitate lines of experimentation that involve extended incubation (e.g., genetic transfection or chronic drug exposure) while simultaneously being amenable to imaging and electrophysiology at cellular, synaptic, and network levels.

Dorsal Medulla Inspiratory Neurons Contribute to Increased Inspiratory Drive during Swallow

Schluckatmung, or swallow breath is believed to be an evolutionarily preserved inspiratory drive from deglutition to eupnea. This inspiratory motor drive creates a net negative trans‐esophageal pressure that promotes bolus movement across the upper esophageal sphincter. A multi‐channel electrode array was used to record dorsal respiratory group neurons in anesthetized, spontaneously breathing cats. Swallowing was induced by injection of water into the oropharynx. Electromyograms (EMG) were recorded from pharyngeal, laryngeal, and chest wall muscles, and intra‐esophageal pressure was recorded from the mid‐thoracic esophagus. A total of 104 inspiratory (I) and expiratory (E) phasic neurons were recorded in 6 animals during breathing and swallow. Approximately 90% of I neurons increased their firing frequency during swallow, and approximately 80% of E neurons decreased their firing frequency during swallow. The increased firing rate of I neurons was associated with costal diaphragm and parasternal EMG bursts along with a negative esophageal pressure during swallow. Previous work has shown low activity of I neurons during swallow in the ventral respiratory column. We conclude that increased dorsal medullary inspiratory neuron activity contributes to enhanced inspiratory drive during swallow. Supported by HL 111215(K99/R00) & HL 103415

Preinspiratory calcium rise in putative pre‐Bötzinger complex astrocytes

The neural inspiratory activity originates from a ventrolateral medullary region called the pre-Bötzinger complex (preBötC), yet the mechanism underlying respiratory rhythmogenesis is not completely understood. Recently, the role of not only neurons but astrocytes in the central respiratory control has attracted considerable attention. Here we report our discovery that an intracellular calcium rise in a subset of putative astrocytes precedes inspiratory neuronal firing in rhythmically active slices. Functional calcium imaging from hundreds of preBötC cells revealed that a subset of putative astrocytes exhibited rhythmic calcium elevations preceding inspiratory neuronal activity with a time lag of approximately 2 s. These preinspiratory putative astrocytes maintained their rhythmic activities even during the blockade of neuronal activity with tetrodotoxin, whereas the rhythm frequency was lowered and the intercellular phases of these rhythms were decoupled. In addition, optogenetic stimulation of preBötC putative astrocytes induced firing of inspiratory neurons. These findings raise the possibility that astrocytes in the preBötC are actively involved in respiratory rhythm generation in rhythmically active slices.

Tonic and phasic drive to medullary respiratory neurons during periodic breathing

It is unknown how central neural activity produces the repetitive termination and restart of periodic breathing (PB). We hypothesized that inspiratory and expiratory neural activities would be greatest during the waxing phase and least during the waning phase. We analyzed diaphragmatic and medullary respiratory neural activities during PB in intact unanesthetized adult cats. Diaphragmatic activity was increased and phasic during the waxing phase and was decreased and tonic during the waning phase. Activity of expiratory (n=21) and inspiratory (n=40) neurons was generally increased and phasic during the waxing phase and was decreased and more tonic during the waning phase. During apneas associated with PB, diaphragmatic activity was silent and most, but not all, inspiratory cells were inactive whereas most expiratory cells decreased activity but remained tonically active. We suggest that reduced strength of reciprocal inhibition, secondary to reduced respiratory drive, allows for simultaneous tonic activity of inspiratory and expiratory neurons of the central pattern generator, ultimately resulting in central apnea.

Brainstem respiratory chemosensitivity: New insights and clinical implications

<h3>Abstract</h3> <h3>Objective</h3> To characterise the umbilical cord blood immune profile in preterm infants compared to term-born controls and the postnatal immune response following exposure to histologic chorioamnionitis (HCA) in preterm infants. <h3>Design</h3> Descriptive, observational cohort study. <h3>Setting</h3> Edinburgh, UK. <h3>Population</h3> 118 preterm infants (mean gestational age 29⁺⁰ weeks, range 23⁺² to 32⁺⁰) and 59 term-born controls. <h3>Methods</h3> Placental histopathology was used to identify reaction patterns indicative of HCA, and a customised immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group. <h3>Results</h3> The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242×10⁻¹⁴. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 5 immune proteins on postnatal day 5 (BDNF, C3, IL-8, MIP-1β and MMP-9) when compared to preterm infants who were not exposed. <h3>Conclusion</h3> Preterm birth is associated with a distinct immune profile in umbilical cord blood and infants exposed to HCA experience specific alterations in immune function that persist to day 5 of postnatal life.

Effects of midline sagittal sectioning of medulla on pre-inspiratory and inspiratory neuron activity in vitro

Effects of midline sagittal sectioning of medulla on pre-inspiratory and inspiratory neuron activity in vitro

Sevoflurane Depresses Glutamatergic Neurotransmission to Brainstem Inspiratory Premotor Neurons but Not Postsynaptic Receptor Function in a Decerebrate Dog Model

Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive motoneurons, which innervate pump muscles such as the diaphragm and external intercostals. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and is modulated by an inhibitory gamma-aminobutyric acid type A (GABAA)ergic input. The authors investigated the effect of sevoflurane on these synaptic mechanisms in decerebrate dogs. Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration sevoflurane on extracellularly recorded activity of single neurons was measured during localized picoejection of the GABAA receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABAAergic mechanism by bicuculline allowed differentiation between the effects of sevoflurane on overall GABAAergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission. One minimum alveolar concentration sevoflurane depressed the spontaneous activity of 23 inspiratory premotor neurons by (mean +/- SD) 30.0 +/- 21.0% (P < 0.001). Overall glutamatergic excitation was depressed 19.2 +/- 18.5% (P < 0.001), whereas overall GABAAergic inhibition was enhanced by 11.9 +/- 25.1% (P < 0.05). The postsynaptic responses to exogenous AMPA and NMDA did not change. One minimum alveolar concentration depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation and an increase in overall inhibition. The postsynaptic AMPA and NMDA receptor response was unchanged. These findings contrast with studies in inspiratory premotor neurons where halothane did not change overall inhibition but significantly reduced the postsynaptic glutamate receptor response.

Sevoflurane Enhances γ-Aminobutyric Acid Type A Receptor Function and Overall Inhibition of Inspiratory Premotor Neurons in a Decerebrate Dog Model

Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic gamma-aminobutyric acid type A (GABAA)ergic inhibition. In a previous study, 1 minimum alveolar concentration (MAC) sevoflurane depressed overall glutamatergic excitatory drive and enhanced overall GABAAergic inhibitory drive to the neurons. This study investigated in further detail the effects of sevoflurane on GABAAergic inhibition by examining postsynaptic GABAA receptor activity in these neurons. Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC sevoflurane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABAA receptor antagonist bicuculline and the GABAA agonist muscimol. Complete blockade of GABAAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABAA receptor function. One MAC sevoflurane depressed the spontaneous activity of 21 inspiratory premotor neurons by (mean +/- SD) 32.6 +/- 20.5% (P < 0.001). Overall excitatory drive was depressed 17.9 +/- 19.8% (P < 0.01). Overall GABAAergic inhibition was enhanced by 18.5 +/- 18.2% (P < 0.001), and the postsynaptic GABAA receptor function was increased by 184.4 +/- 121.8% (n = 20; P < 0.001). One MAC sevoflurane greatly enhanced GABAA receptor function on inspiratory premotor neurons and increased overall synaptic inhibition but to a smaller extent, indicating that the presynaptic inhibitory input was also reduced. Therefore, the anesthetic depression of spontaneous inspiratory premotor neuronal activity by 1 MAC sevoflurane in vivo is due to a combined effect on the two major ionotropic synaptic neurotransmitter systems with a decrease in overall glutamatergic excitation and a strong enhancement of postsynaptic GABAA receptor function.

Pbx3 Deficiency Results in Central Hypoventilation

Pbx proteins comprise a family of TALE (three amino acid loop extension) class homeodomain transcription factors that are implicated in developmental gene expression through their abilities to form hetero-oligomeric DNA-binding complexes and function as transcriptional regulators in numerous cell types. We demonstrate here that one member of this family, Pbx3, is expressed at high levels predominantly in the developing central nervous system, including a region of the medulla oblongata that is implicated in the control of respiration. Pbx3-deficient mice develop to term but die within a few hours of birth from central respiratory failure due to abnormal activity of inspiratory neurons in the medulla. This partially phenocopies the defect in mice deficient for Rnx, a metaHox homeodomain transcription factor, that we demonstrate here is capable of forming a DNA-binding complex with Pbx3. Rnx expression is unperturbed in Pbx3-deficient mice, but its ability to enhance transcription in vitro as a complex with TALE proteins is compromised in the absence of Pbx3. Thus, Pbx3 is essential for respiration and, like its DNA-binding partner Rnx, is critical for proper development of medullary respiratory control mechanisms. Pbx3-deficient mice provide a model for congenital central hypoventilation syndrome and suggest that Pbx3 mutations may promote the pathogenesis of this disorder.

Halothane enhances gamma-aminobutyric acid receptor type A function but does not change overall inhibition in inspiratory premotor neurons in a decerebrate dog model.

Inspiratory premotor neurons in the caudal ventral medulla relay excitatory drive to phrenic and inspiratory intercostal motoneurons in the spinal cord. These neurons are subject to tonic gamma-aminobutyric acid type A (GABA(A))-mediated (GABA(A)ergic) inhibition. In a previous study, 1 minimum alveolar concentration (MAC) halothane depressed overall glutamatergic excitatory drive but did not change overall inhibitory drive to the neurons. This study investigated in further detail the effects of halothane on GABA(A)ergic inhibition by examining postsynaptic GABA(A) receptor activity in these neurons. Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 MAC halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABA(A) receptor antagonist bicuculline and the GABA(A) agonist muscimol. Complete blockade of GABAergic inhibition by bicuculline allowed estimation of the prevailing overall inhibition of the neuron. The neuronal response to muscimol was used to assess the anesthetic effect on the postsynaptic GABA(A) receptor function. One minimum alveolar concentration halothane depressed the spontaneous activity of 19 inspiratory premotor neurons by 22.9 +/- 29.1% (mean +/- SD; P < 0.01). Overall excitatory drive was depressed 23.6 +/- 16.9% (P < 0.001). Overall GABAergic inhibition was not changed (+8.7 +/- 27.5%; P = 0.295), but the postsynaptic GABA(A) receptor function was increased by 110.3 +/- 97.5% (P < 0.001). One minimum alveolar concentration halothane greatly enhanced GABA(A) receptor function on inspiratory premotor neurons but did not change overall synaptic inhibition, indicating that the presynaptic inhibitory input was reduced. Therefore, the anesthetic depression of spontaneous inspiratory premotor neuronal activity in the intact brainstem respiratory network is mainly due to a decrease in overall glutamatergic excitation.

Halothane depresses glutamatergic neurotransmission to brain stem inspiratory premotor neurons in a decerebrate dog model.

Inspiratory bulbospinal neurons in the caudal ventral medulla are premotor neurons that drive phrenic motoneurons and ultimately the diaphragm. Excitatory drive to these neurons is mediated by N-methyl-d-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors and modulated by an inhibitory gamma-aminobutyric acid(A) (GABA(A))ergic input. The authors investigated the effect of halothane on these synaptic mechanisms in decerebrate dogs. Studies were performed in decerebrate, vagotomized, paralyzed, and mechanically ventilated dogs during hypercapnic hyperoxia. The effect of 1 minimum alveolar concentration (MAC) halothane on extracellularly recorded neuronal activity was measured during localized picoejection of the GABA(A) receptor blocker bicuculline and the glutamate agonists AMPA and NMDA. Complete blockade of the GABA(A)ergic mechanism by bicuculline allowed differentiation between the effects of halothane on overall GABA(A)ergic inhibition and on overall glutamatergic excitation. The neuronal responses to exogenous AMPA and NMDA were used to estimate the anesthetic effect on postsynaptic glutamatergic neurotransmission. Halothane, 1 MAC, depressed the spontaneous activity of 21 inspiratory neurons by 20.6 +/- 18.0% (mean +/- SD; P = 0.012). Overall glutamatergic excitation was depressed 15.4 +/- 20.2% (P = 0.001), while overall GABA(A)ergic inhibition did not change. The postsynaptic responses to exogenous AMPA and NMDA were also depressed by 18.6 +/- 35.7% (P = 0.03) and 22.2 +/- 26.2% (P = 0.004), respectively. Halothane, 1 MAC, depressed the activity of inspiratory premotor neurons by a reduction of glutamatergic excitation. Overall inhibitory drive did not change. The postsynaptic AMPA and NMDA receptor response was significantly reduced. These findings contrast with studies in expiratory premotor neurons in which overall inhibition was significantly increased by halothane and there was no reduction in the postsynaptic glutamate receptor response.

Respiratory-modulated neuronal activities of the rostral medulla which may generate gasping.

Different neurophysiological mechanisms have been proposed to generate eupnea and gasping. Gasping is generated by neuronal mechanisms intrinsic to the medulla whereas a ponto-medullary neuronal circuit has been hypothesized to generate eupnea. Hence, neurons in the rostral medullary region which are critical for the neurogenesis of gasping are hypothesized to discharge differently in eupnea and gasping. In a perfused in situ preparation of the juvenile rat, these rostral medullary neuronal activities had inspiratory, expiratory and phase-spanning patterns in eupnea. In gasping, most expiratory and phase-spanning activities ceased, whereas many inspiratory neuronal activities changed to a decrementing pattern as that of the phrenic nerve. A limited proportion of neuronal activities acquired a 'pre-inspiratory' discharge in gasping. These neuronal activities, which were inspiratory or phase-spanning in eupnea, commenced discharge in neural expiration. This discharge peaked at the onset of the gasp and then decremented during neural inspiration. We hypothesize that these 'pre-inspiratory' neuronal activities generate the gasp by intrinsic pacemaker mechanisms.

Salicylate action on medullary inspiratory neuron activity in a brainstem-spinal cord preparation from newborn rats.

Salicylate affects central respiratory control. The inspiratory neurons are the most important component of the medullary respiratory control center because they modulate the final motor output via the phrenic nerve. We investigated changes in burst rate, intraburst firing frequency, and membrane properties of inspiratory neurons in the isolated brainstem after the administration of salicylate. Newborn rat brainstem-spinal cord preparations were superfused with salicylate. Whole-cell recordings were performed from inspiratory neurons. Application of 1 mM salicylate caused an increase in the inspiratory neuronal burst rate from 6.9 +/- 1.6 bursts/min to 8.2 +/- 1.9 bursts/min (P < 0.05). The inspiratory neuron burst rate decreased from 8.3 +/- 0.7 bursts/min to 4.5 +/- 1.1 bursts/min after the application of 10 mM salicylate (P < 0.01). The depressant effect of 10 mM salicylate was antagonized by the gamma-aminobutyric acid (GABA) receptor antagonist bicuculline (1 microM). Resting membrane potential and intraburst firing frequency did not change with the application of salicylate and bicuculline even when the burst rate did change. We conclude that the effects of salicylate on the medullary inspiratory neurons are mainly due to a presynaptic action. GABAergic mechanisms are probably involved in the salicylate-induced central respiratory depression.

Salicylate Action on Medullary Inspiratory Neuron Activity in a Brainstem-Spinal Cord Preparation from Newborn Rats

Salicylate Action on Medullary Inspiratory Neuron Activity in a Brainstem-Spinal Cord Preparation from Newborn Rats